Effectiveness and cost-effectiveness of lymphaticovenous anastomosis for cancer patients who suffer from chronic peripheral lymphedema

Lymphedema is a chronic and progressive disorder caused by disruption or
dysfunction of the lymphatic system. It is marked by the progressive
accumulation of protein-rich fluid within the interstitium and fibro-adipose
tissue, which ultimately exceeds the capacity of the lymphatic system to
transport fluid. This fluid overload leads to fibrosis, due to stromal and
parenchymal proliferation and excessive deposition of the extracellular matrix.
Swelling associated with lymphedema can occur anywhere, including arms, legs,
genitals, face, neck, chest wall, and oral cavity. However, it is predominantly
observed in the upper and lower extremities.

Lymphedema can be congenital or acquired. Congenital or primary lymphedema is a
rare disorder caused by genetic mutations that leads to underdevelopment or
dysfunction of the lymphatic system. Whereas acquired or secondary lymphedema
is a consequence of trauma, systemic disease, infection, or surgery. In
developed countries, the most frequent cause of secondary lymphedema is a
result of oncological treatment for several solid tumors, including breast,
melanoma, head and neck, gynecological, and genitourinary malignancies.

The time course for the development of lymphedema after cancer treatment is
dependent on the extensiveness of the treatment received. In BRCL the risk of
lymphedema was the highest after 12-30 months post-operatively. After
gynecological cancers, the highest onset frequency was reported after the first
year of the cancer diagnosis. In the case of lymphedema after melanoma the
highest frequency of lymphedema was reported after one year.

Cancer-related lymphedema has an overall incidence of 15.5% and is highest in
patients receiving radiation therapy (31%). According to Cormier et al. (2010),
the pooled incidence of lymphedema in cancer was 15.5% with an individual
incidence of 16% in melanomas (5% upper extremity and 28% lower extremity), 20%
in gynecological cancer i.e endometrial cancer, vulva cancer and ovarian
cancer, 10% in urogenital cancers and 30% in sarcomas in the upper and lower
extremity.

In the Netherlands, around 15.000 women develop breast cancer each year of
which around 25% (3.750 patients) develop lymphedema. For cervix and ovarian
cancer, 30-50% of 2.100 cases each year develop lymphedema which is between 600
and 1.050 patients. Lymphedema after bladder, prostate, or male genitalia
cancer develops lymphedema in 15-30% of around 21.300 cases which are between
3.195 and 6.390 patients.

Given the lack of standardized diagnostic criteria, diagnosis of lymphedema is
based primarily on presentation and examination findings. Limb volume
measurements using a tape measure, water displacement, perometry, bioimpedance,
and lymphoscintigraphy can corroborate the diagnosis. An increase in limb
volume of <10% in comparison to the healthy extremity can indicate
(sub)clinical lymphedema. The severity of lymphedema is categorized as mild
(<20% increase in extremity volume), moderate (20-40%), or severe (>40%).
Up until now, the most common classification is the clinical classification of
lymphedematous swelling defined by the International Society of Lymphology
(ISL). Furthermore, the near-infrared fluorescence imaging (NIRF) with
indocyanine green (ICG) is used to determine the dermal backflow stage as
standard care in the out-patient clinic. NIRF also makes it possible to assess
if a patient has viable lymphatics for LVA surgery.

Patients with CRL not only suffer from the physical but also the psychosocial
consequences of lymphedema. The physical symptoms include swelling, heaviness
of the extremity, pain, paresthesia, reduced range of motion, and weakness.
Particularly, lower extremity lymphedema (LEL) may also evoke immobility,
ulcers/skin breakages, and weeping of the lymphedematous region. Patients with
lymphedema have a higher propensity for cellulitis and erysipelas infections.
CRL is also associated with psychosocial symptoms such as depression, anxiety,
and difficulty in social, domestic, vocational, and sexual domains. To manage
symptoms and prevent disease progression lifelong maintenance is required which
results in a radical adjustment of daily living (ADL) to comply with treatment.
Patients with CRL also experience financial repercussions due to treatment
costs but also due to the inability to work following lymphedema onset are not
without financial repercussions.

To this date, there is no definite cure for lymphedema. Currently, conservative
therapy, namely complex decongestive therapy is the golden standard for the
treatment. Complex decongestive therapy consists of manual lymphatic drainage,
compression therapy, and skin/wound care. CDT is often indicated in patients
with more than 5-10% excess volume starting with compression stockings.

At the beginning of this millennium microvascular surgery was developed and
anastomoses in vessels as small as 0.3mm in diameter were made possible. This
meant the beginning of *super microsurgery*. Because of these technical
refinements, it is now possible to create multiple bypasses between lymphatic
vessels (ranging from 0.3 mm - 0.8 mm) and smaller venular vessels (< 0.8 mm)
with lower pressure than previously possible. These venules and lymphatic
vessels can be found in the subdermal plane. The minimal invasiveness of this
procedure is another advantage, as it can be performed under local anesthesia.
Usually, 1 to 4 anastomoses are made at several points within a lymphedema arm.
LVA surgery aims to reduce arm volume, reduce episodes of cellulitis,
discontinuation of compressive garments, and most importantly regain the
ability to participate in social activities and ultimately improve the quality
of life. With the advancement of super microsurgery, LVA is gaining traction as
an effective surgical treatment for extremity lymphedema.

Multiple studies have evaluated the safety and efficacy of LVA surgery in the
extremities. These studies report a volume-reductive effect between 6% and 85%.
However, the success rate is dependent on multiple factors such as technique
and lymphedema stage. Chang et al. published results on a prospective study
concerning 30 patients with BCRL. After 1-year follow-up, a mean reduction of
61% in the early-stage group (MD Anderson stage I or II) was reported, whereas
a mean reduction of 17% in the late-stage group (MD Anderson stage III or IV)
was presented. Overall, 96% of the patients presented subjective improvement in
their symptoms. Cornelissen et al. prospectively performed a study on the
improvement in quality of life after LVA in women with BCRL. They found a
decrease in circumference, although not statistically significant. Furthermore,
a statistically significant improvement in Lymph-ICF scores after 1-year of
follow-up using a validated questionnaire (Lymphoedema Functioning, Disability
and Health). Moreover, 85% of the patients discontinued compressive stockings.
Winters et al. performed a retrospective study on the efficacy of LVA in BCRL
on 29 patients. After 1-year follow-up, the percentage volume reduction was
33%. Only one patient showed an increase in volume. The overall perceived
quality of life also increased. Fifteen patients were able to discontinue the
use of compression garments.

For the lower extremity, a systematic review conducted by Rosian et al. has
shown positive outcomes, however, there is variation in limb size reduction.
This is often dependent on the severity of lymphedema, the amount of
anastomosis along with the risk factors associated with lymphedema. The highest
reduction rates reported after LVA ranged between 51.1% and 63.8%, with better
results achieved in the early stages of lymphedema.
Another systematic review conducted by Verhey et al. included 74 studies
analyzing the efficacy of LVA in patients with lower extremity lymphedema and
reported an overall average reduction in limb volume of 22.67%, and a reduction
of excess limb volume of 45.52%. Overall complications were rare with a
postoperative pelvic reoccurrence of lymphedema in one out of 10 patients,
postoperative infections in two out of 12 patients, and subcutaneous ecchymosis
in 6 patients overall. Conversely, 15 out of 74 studies noted a complete or
partial reduction of cellulitis. Concurrently, a meta-analysis by Basta et al.
reported low incidences of minor complications. Complications reported are not
different from the standard complications which can be expected after this
small surgery (infection and bleeding). Furthermore, an improvement of
subjective symptoms such as a reduction in pain, heaviness, sense of anxiety,
and increased self-confidence and self-esteem was seen in 90% of the
population.

Overall, a systematic review and meta-analysis by Nacchiero et al. corroborated
the abovementioned data that LVA can result in statistically significant
improvement of outcomes such as limb volume, arm circumference, and QOL.
However, until now the studies available are small non-randomized studies and
the quality of the studies is lacking. Furthermore, there is a large
variability in outcome measures and mixed results. No large-scale prospective
or randomized studies have been published on the efficacy of LVA.

Based on the findings that:
a) Chronic CRL is associated with ADL impairment, a strong negative
psychosocial impact, and reduced quality of life
b) CRL is a progressive and chronic disease
c) Treatment in the early phase of CRL increases treatment effectivity
d) Current (conservative) treatment is not aimed at repairing the impaired
lymphatic function
e) Lymphatic microsurgery is one of the treatments that may help regain normal
lymphatic function,
We have formulated the following hypotheses that will be studied in this
project:

Patients undergoing lymphatic microsurgery for persistent CRL will have:
1) Higher Lymph-ICF and EQ5D scores,
2) Less ELV (measured by bioimpedance and circumference measurement).

Pilot data MUMC+
Since 2015 the Department of Plastic and Reconstructive surgery at the
Maastricht University Medical Center (MUMC) has been conducting studies on the
effect of LVA surgery, headed by dr. Qiu Shao.
Qiu et al. conducted a prospective trial on the efficacy of LVA surgery in
patients with secondary lymphedema. In this study, 100 patients were included
with upper and lower extremity lymphedema. A statistically significant increase
in the total Lymph-ICF score was reported after 2 years, measured with the
validated Lymph ICF questionnaire. Overall mean circumference was not
significantly different. The percentage of patients that could reduce
compression garments in the upper and lower extremity group was 65% and 40%,
respectively. Number of cellulitis episodes per year and MLD sessions per week
showed a mean decrease of respectively 0.6 and 0.8 in the upper extremity and
0.4 and 1.0 in the lower extremity group.

Furthermore, Wolfs et al. (2019) assessed long-term patency in 25 women with
BRCL who received LVA surgery, with a total of 47 anastomoses. In the current
study, in three-quarters of patients, at least one anastomosis was considered
patent. Compared with the non-patent group, the patent anastomosis group showed
more improvement in QoL, a decrease in arm circumference, and a higher
discontinuation rate of compression stockings, indicating a conceivable
positive correlation between a patent anastomosis and clinical improvement
after LVA .

A RadboudUMC pilot study (2017) with 29 patients also showed a statistically
significant increase in HRQoL (from 5.8±1.1 to 7.4±0.7; p=0.00) measured by the
LYMQOL questionnaire (scored between 0 as the worst and 10 as best), 54%
discontinued compression stockings.

Since 2018 the *Veelbelovende Zorg* subsidized (ZonMw 852001904) *The Lymph
Trial* is being conducted, a randomized controlled trial on the (cost)
effectiveness of LVA surgery in comparison to CDT in patients with BRCL
(NL67059.068.18/ METC 18-024). In this trial, the primary outcome is HrQOL
measured by the Lymph-ICF. The secondary outcome measures are excess limb
volume, cost-effectiveness, and discontinuation of MLD and compressive
garments. The one-year result will be available in 2024.

The N-LVA study will be an extension of the current study, where patients with
CRL of the upper and lower extremity with viable lymph vessels will be
included. To compensate for the placebo/sham effect, a double-blind
sham-controlled trial is proposed in concordance with *Veelbelovende
zorg* (ZonMw) main subsidy provider of this trial.

Primary Objective:
The primary objective is to assess the efficacy of LVA surgery in comparison to
sham procedure in patients with cancer related lymphedema in the context of
improvement of Lymph-ICF score at 12 and 24 months follow up.

Secondary Objectives:
- To assess the effect of LVA on excess limb volume compared to sham
procedure;
- To determine the discontinuation rate of conservative treatment after LVA and
Sham procedure (the percentage of patients who will be independent of
compression stockings and the percentage of patients who will discontinue MLD);
- To assess the cost-effectiveness of LVA.

All endpoints set at 12 and 24 months. All the included patients will be
continue followed until the start of the first analysis.
*

A multicenter, double-blinded, randomized sham-controlled trial (RCT). Patients
will be included in the Maastricht University Medical Centre, Radboud
University Medical Centre, and Erasmus Medical Center. There are two study
groups. The first group will receive LVA surgery and the second group will
receive a sham surgery. The total duration of the study is 72 months. Inclusion
period will take maximally 36 months. The follow-up will last 24 months. The
last 6 months will be used for data analysis and writing the end report.
Due to the nature of the study the surgeon performing the both procedures will
not be blinded. Both the researcher and/or research nurse and patients will be
blinded for the study. The blinded researchers will perform the measurements
during follow up.

Adult patients with refractory, cancer-related lymphedema in the upper or lower
extremity, who are eligible for surgery, will be randomly allocated to one of
the two treatment groups:
1. LVA group;
2. Sham group.

Group 1. Lymphaticovenous anastomosis (LVA):
LVA involves anastomosing lymphatic vessels (0.3 to 0.5 millimetres in
diameter) to small veins in the subdermal plane to bypass obstructions of the
lymphatic transport. The surgical technique follows the technique of other
international surgeons.
Before the start of the surgery, the patient will be blinded with
noise-cancelling headphones and blindfolds. Then the patient lies comfortably
on the operation table, after which the affected limb is prepared for surgery.
A limb table is used. Before marking the incision, a mix of bupivacaine
(Marcaïne®) and epinephrine (1:100.000) is injected at the site of the incision
to achieve local anaesthesia and optimal hemostasis. Based on the ICG
lymphangiography mapping, incisions of 1, 5 to 2 cm are made at the
predetermined sites. The incisions are made at the level where the lymphatic
vessels are obstructed to prevent any damage to the viable part of the
lymphatic system. Using a surgical microscope (25-40x magnification), the
lymphatic vessels are visually identified. When a viable lymphatic vessel is
identified, it is anastomosed to a similarly sized adjacent recipient venule in
the subdermal plane. The anastomoses are usually made in an end-to-end fashion
when both the lymphatic vessel and venule have about the same caliber,
otherwise, an end-to-side anastomosis is made. The end-to-end anastomoses are
created with an 11-0 or 12-0 suture, indicating the need for advanced,
supermicrosurgical instruments. The patency of the LVA is confirmed by direct
visual examination under the microscope. Generally, 1 to 4 anastomoses are made
in a lymphedematous extremity. The superficial wound is closed using
uninterrupted, intracutaneous sutures, using 4-0 Monocryl, and is covered with
adhesive plasters and a bandage. The total operation time is approximately one
to three hours.

Group 2. Sham procedure:
As with the LVA operation, the patient is also blinded during the surgery,
using noise-cancelling headphones and a blindfold. The set-up for the surgical
floor will be identical to the regular surgery, with a surgical microscope,
supermicrosurgical instruments, and designated surgical personnel. Local
anesthesia is used to numb the predetermined sites, whereafter a shallow
incision of the dermis of 1,5 to 2 cm is made. After the incision, no LVA is
made. To mimic the approximate duration of a regular LVA procedure, the sham
operation will then take approximately one to one and a half hours. At the end
of the procedure, the superficial wound is closed in the same manner as in the
LVA procedure; with uninterrupted, intracutaneous sutures, using 4-0 Monocryl
and covered with adhesive plasters and a bandage.

In the context of the study, the following measurement moments are included:

- Introductory interview: ICG Lymphography to determine whether the candidate
is suitable. In patients with lymphedema of the lower extremities,
lymphscintigraphy is also performed and possibly an echo Doppler to
confirm/exclude the diagnosis.
- First interview with researcher: Lymph-ICF questionnaire and EQ-5D-5L
questionnaire (digital), this takes approximately 10 minutes.
Weight, height and other relevant patient characteristics are recorded in the
EHR. Circumference measurements with tape measure, this takes 3-5 minutes.
Bio-impedant spectroscopy, takes about 15 minutes. Completing the patient diary
(digital), takes 5 minutes.
- Intervention: LVA or sham procedure, duration approximately 1.5 hours.
- 3 months follow-up: Lymph-ICF questionnaire and EQ-5D-5L questionnaire
(digital). Weight, height and other relevant patient characteristics are
recorded in the EHR. Circumference measurements with tape measure. Bioimpedant
spectroscopy. Complete patient diary (digital).
- 6 months follow-up: Lymph-ICF questionnaire and EQ-5D-5L questionnaire
(digital). Weight, height and other relevant patient characteristics are
recorded in the EHR. Circumference measurements with tape measure. Bioimpedant
spectroscopy. Complete patient diary (digital).
- 12 months follow-up: Lymph-ICF questionnaire and EQ-5D-5L questionnaire
(digital). Weight, height and other relevant patient characteristics are
recorded in the EHR. Circumference measurements with tape measure. Bioimpedant
spectroscopy. Complete patient diary (digital). Also ICG Lymphography to assess
whether anastomoses are patent.
- 18 months follow-up: Lymph-ICF questionnaire and EQ-5D-5L questionnaire
(digital). Weight, height and other relevant patient characteristics are
recorded in the EHR. Circumference measurements with tape measure. Bioimpedant
spectroscopy. Complete patient diary (digital).
- 24 months follow-up: Lymph-ICF questionnaire and EQ-5D-5L questionnaire
(digital). Weight, height and other relevant patient characteristics are
recorded in the EHR. Circumference measurements with tape measure. Bioimpedant
spectroscopy. Complete patient diary (digital). Also ICG Lymphography to assess
whether anastomoses are patent.

Risks:
The lymphscintigraphy examination entails minimal radiation exposure. However,
this examination is also part of regular patient care.
With ICG Lymphography, ICG fluid is injected, which can be painful for a short
time.
The risk and chance of complications of LVA (and the sham procedure) are low,
as the lymph vessels used are already damaged. The healthy lymphatic tissue is
spared. Further, the procedure takes place in the subcutaneous layer of the
skin to a depth of 1.5 cm. No major vessels or other structures are present at
this level, minimizing the risk of bleeding or infection. At the latest, the
procedure can be performed under local anesthesia. All things considered, the
risks and burden for the patient are low and acceptable.